JP2020094008A - Drug delivery system containing metal acene complex - Google Patents

Abstract

To provide a novel drug delivery system containing an organic compound-based magnetic support.SOLUTION: An drug delivery system composition is for delivering a drug to a target tissue while surviving the target tissue, the composition containing a structure of a halogenated metal acene complex or a metal acene complex dimer as a magnetic support.SELECTED DRAWING: Figure 1

Description

The present disclosure relates to systems for delivering drugs in vivo or in tissues.

A system for delivering a drug to a target site in the body where the action of the drug is required is generally called a drug delivery system (DDS). DDS technologies include those related to drug administration routes, controlled release, metabolic control, toxicity control, targeting, and the like.

One example of the most typical and well-studied DDS is liposomes. Liposomes can encapsulate various compounds regardless of whether they are water-soluble or fat-soluble (encapsulation also includes the case where compounds are bound to the liposome lipid layer itself), and high molecular weight molecules such as proteins and nucleic acids can also be encapsulated. These substances can be delivered while avoiding significant degradation and absorption. Further, the surface can be modified with a polyethylene glycol chain for improving blood stability, a sugar chain for imparting a targeting property or other functions, an antibody, various ligands and the like. Furthermore, by co-encapsulating a magnetic material in the liposome, it is possible to use magnetic force to impart targeting property (Non-Patent Document 1).

There is also known a technique in which the active drug molecule itself is provided with magnetism (hereinafter, simply referred to as “magnetism”) that enables position induction by applying a magnetic field. For example, Patent Documents 1 to 5 describe antitumor drugs containing a metal-salen complex or a metal-acene complex having self-magnetism as an antitumor activity (cell-killing activity) component.

Further, a technique is also known in which a specific organic compound having magnetism is covalently linked to an active drug molecule. Non-Patent Document 2 describes an antitumor drug in which a metal salen complex having automagnetism and antitumor activity is further linked to another antitumor compound. Fe ₃ O ₄ and FePt are more commonly used as magnetic materials for delivering other drugs, but the metal-salen complex can simultaneously provide not only magnetic properties but also antitumor properties, and the structural characteristics of organic compounds. It is characterized by the ability to provide modification and degradation characteristics.

Further advantages common to these magnetic drugs and magnetic carriers are that the pharmacokinetics after administration can be tracked by MRI and the like, and it is also possible to generate heat in the body by applying an alternating magnetic field. .

Since the metal complexes described in the above-mentioned documents have magnetism and strong cytotoxicity (cell killing activity), they are suitable for use in antitumor drugs. That is, when a metal complex is induced to the affected area by applying a magnetic field from outside the body after administering a composition containing any of these metal complexes to a living body, the cell-killing activity is locally concentrated. However, these metal complexes are not suitable for use as targeting DDS carriers for drugs that are not necessarily aimed at killing the target tissue.

Japanese Patent No. 5167481 Japanese Patent No. 4446489 Japanese Patent No. 5461968 Japanese Patent No. 5680065 Japanese Patent No. 6017766

YAKUGAKU ZASSHI, 128(2), 185-186 (2008) Oncotarget, 2018, 9(21):15591-15605 and Supplementary Files.

There is a need for drug delivery systems that include organic compound-based magnetic carriers that can provide additional variations in structure, magnetism, and/or cytotoxicity. The embodiments of the present disclosure provide a novel drug delivery system that meets such needs.

We have found that when halogenated or dimerized metal acene complexes have significant magnetic properties compared to their non-halogenated and non-dimerized counterparts and their salen complex counterparts. It was found to be enhanced and the cytotoxicity was significantly reduced. Moreover, they have found that other agents can be effectively linked to the metal halide acene complex and the metal acene complex dimer. The embodiments of the present disclosure are based on these findings.

The present disclosure includes the following embodiments.
[1]
A drug delivery system composition for delivering a drug to a target tissue while allowing the target tissue to survive, comprising:
Formula (I) below:
Or the following formula (II):
A metal acene complex structure represented by the following is included as a magnetic carrier, in which A is a halide ion, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os. , Ir, Pt, Nd, Sm, Eu, and Gd, which is a metal ion selected from the group consisting of:
Composition.
[2]
The composition according to [1], wherein M is Fe, Mn, Cr, or Cu.
[3]
A drug delivery system composition for delivering a drug to a target tissue while allowing the target tissue to survive, comprising:
The following formula (I')
Or the following formula (II')
In the formula, the wavy line is a bonding point, A is a halide ion, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, A metal ion selected from the group consisting of W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd,
Composition.
[4]
Formula (III) below:
Or the following formula (IV):
A metal acene complex represented by
A is a halide ion,
M is a metal ion selected from the group consisting of Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd,
R ^{1 to} R ⁶ are each a hydrogen atom or a linker group derived from a linker compound having a group capable of forming a bond with a hydroxy group,
O ^* is an oxygen atom derived from a hydroxy group on the metal acene complex and forms a hydroxy group with the hydrogen atom, or forms a bond with the linker compound,
At least one of R ¹ and R ² , and at least one of R ^{3 to} R ⁶ is a linker group bonded to the drug at a terminal other than the terminal bound to the O ^*. ,
The composition according to [3].
[5]
The composition according to [3] or [4], wherein M is Fe, Mn, Cr, or Cu.
[6]
The composition according to [4], wherein the linker group bonded to the drug at a terminal other than the terminal bound to the O ^* is bonded to the drug via a sulfhydryl group on the drug.
[7]
Of R ^{1 to} R ^6, the linker group bonded to the drug has a structure represented by the following formula (V):
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure of a linker group represented by the following formula (VI),
In the formula, * represents a bond to the O ^* , X is the bonded drug, and S is a sulfur atom derived from the sulfhydryl group,
The composition according to [6].
[8]
The composition according to [4], wherein a linker group bonded to the drug at a terminal other than the terminal bonded to the O ^* is bonded to the drug via an amino group on the drug.
[9]
Of R ^{1 to} R ^6, the linker group bonded to the drug has a structure represented by the following formula (VIII),
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure of a linker group represented by the following formula (IX),
In the formula, * represents a bond to the O ^* , X is the bonded drug, and N ^** is a nitrogen atom derived from the amino group,
The composition according to [8].

The embodiments of the present disclosure can provide a drug delivery system including a magnetic carrier based on an organic compound having strong magnetism and low cytotoxicity.

FIG. 1 shows the results of magnetic property evaluation of the iron-acene complex dimer (a) and the iron chloride-acene complex (b), in comparison with the results obtained from the iron-salen complex dimer. FIG. 2 shows the cell-killing activity of iron-acene complex dimers and iron chloride-acene complexes on human ovarian cancer cells, in comparison with that of iron-salen complex dimers. FIG. 3 shows the powder X-ray measurement results of the iron chloride acene complex and the iron acene complex dimer, together with the corresponding theoretical calculated values.

In one aspect of the present disclosure, a drug delivery system composition for delivering a pharmaceutical agent to a target tissue while allowing the target tissue to survive, the metal halide acene complex structure or the metal halide acene complex dimer. Compositions are provided that include a body structure as a magnetic carrier. As is clear from the present disclosure, acene (also referred to as acacen) is a structure related to acetylacetone and should not be mixed with acene, which is a compound in which benzene rings are linearly condensed. By magnetic carrier is meant a magnetic carrier that allows it to be directed to a particular location or area or direction within a subject by application of a magnetic field after administration to the subject. For example, the composition may have the form of liposomes and the magnetic carrier may be encapsulated within the liposomal lipid layer with the agent to be delivered. In another example, as described below, the drug can be linked to the magnetic carrier via a covalent bond. In the present disclosure, bond means covalent bond unless otherwise specified.

In the present disclosure, the "subject" of administration of the composition is preferably an animal individual, more preferably a mammalian individual, and particularly preferably a human individual. However, embodiments are also contemplated in which in vitro cultured tissues are the subject of administration, for example in biomedical research.

The magnetic carrier contained in the composition of the present embodiment has low cytotoxicity or cytotoxicity. Cytotoxic means the activity of killing cells of a subject or inhibiting the growth of cells of a subject. As described in the Examples section, when the human salen complex dimer was administered to the human ovarian cancer cell line OVK18 (available from RIKEN BioResource Research Center etc.) in an amount of 2.5 mg/L and cultured for 17 hours Reduce cell viability by less than 50% compared to untreated controls. This is understood as strong cytotoxicity. A metal complex that can maintain a cell viability of 50% or more under the same dose condition is defined as low cytotoxicity, and a metal complex that can maintain a cell viability of 80% or more is acellular. Is defined. Due to such low cytotoxicity or cytotoxicity, the target tissue can survive.

The magnetic carrier based on the conventional metal complex described above has strong cytotoxicity by itself, and thus it is suitable for delivery for the purpose of killing the target tissue, but for the purpose of delivering the drug while suppressing the cytotoxicity of the magnetic carrier. Was not suitable. On the other hand, the composition of the present embodiment suppresses the cytotoxicity of the magnetic carrier, that is, while preventing the lethality of the target tissue by the magnetic carrier itself, thus allowing the target tissue to survive, the drug based on the magnetism of the magnetic carrier is used. It can be delivered to the target tissue.

In the present disclosure, the “target tissue” is a tissue or a part thereof that constitutes a subject to which a drug is administered and is intended to be a delivery destination of the drug or a part thereof. An organism that is parasitic, infected, or symbiotic in a subject (a different species than the subject) is not the target tissue for the drug delivery system composition, even if it is the target of action of the drug. For example, a bacterial cell that infects a human body as a target is not understood as a "target tissue" even if it is the target of action of a drug, and the "target tissue" is only a human body infected by the bacterium. It is understood to be an organization.

In one embodiment, the drug delivery system composition comprises
Formula (I) below:
A metal halide acene complex structure represented by
Or the following formula (II):
The metal acene complex dimer structure represented by is included as a magnetic carrier. In the formula, A is a halide ion, preferably F, Cl, Br, or I, more preferably Cl or Br, and particularly preferably Cl. M is a metal ion selected from the group consisting of Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd. , Preferably Fe, Mn, Cr, or Cu, and particularly preferably Fe. More preferably, the drug delivery system composition comprises a metal acene complex structure of formula (I) as a magnetic carrier.

In one embodiment, the drug delivery system composition comprises a metal acene complex-drug conjugate in which the metal acene complex of formula (I) or formula (II) above is linked to the drug via a linker structure. The linker structure is preferably bonded to the central carbon atom having no methyl group in the hydrocarbon semicyclic structure connecting N and O in formula (I) or formula (II). Hereinafter, this specific carbon atom is referred to as a linker bond carbon atom. The linker group is preferably bonded to the metal acene complex via an oxygen atom bonded to a carbon atom in the linker bond portion.

The drug delivery system composition may include a compound having a partial structure represented by the following formula (I′) or formula (II′).
Here, the definitions of M and A are as described above for formulas (I) and (II), and the wavy line represents the point of attachment. The point of attachment can be, inter alia, a linker molecule, a drug molecule, or a point of attachment to a hydrogen atom. The drug delivery system composition of this embodiment is characterized in that it contains the above-mentioned partial structure as a magnetic carrier, and the type of the linker and drug to be linked is determined by the user depending on the individual application, and It should be appropriately selected based on ordinary knowledge.

It is known from the Goodenough-Kanamori-Anderson rule that if the bond angle of magnetic ion-anion-magnetic ion is close to 90 degrees, it exhibits ferromagnetism. Furthermore, in a previous study (Non-patent Document 2) in which a linker molecule and a drug were bound to an iron-salen complex dimer, the Fe-O-Fe bond angle, which varies depending on the number of the linker and the drug bound, is 128. It had ferromagnetism in the range of 257 degrees to 171.237 degrees. Similarly, even in the case of a metal acene complex, even when the linker and the drug are bonded, the bond angle of magnetic metal ion-anion-magnetic metal ion is expected to be an angle exhibiting ferromagnetism, and therefore the formula (I) or ( Magnetism is not lost when a linker group and a drug are attached to the structure of II). Further, since it is experimentally clear that neither drug nor linker molecule is toxic, and the acene complex has low cytotoxicity, it is understood that the above metal acene complex-drug conjugate has low cytotoxicity.

As described above, the metal acene complex in which a linker group is bonded via an oxygen atom has a structure in which a hydroxy group is bonded to a carbon atom in the linker bond portion (not necessarily forming a completed metal acene complex, but a metal acene complex Can also be an intermediate for the synthesis). That is, it is understood that a linker compound having a group capable of reacting with a hydroxy group to form a bond can be prepared by reacting with a hydroxy group on the above structure to form a bond. In this case, whether the linker compound is bound to all of a plurality of hydroxy groups or the linker compound is bound to only some of the hydroxy groups can be varied depending on the reaction conditions, and therefore both modes are possible. In the latter case, the hydroxy group to which the linker compound has not been bound may remain as the hydroxy group in the final metal acene complex-drug conjugate. That is, in the final metal acene complex-drug conjugate, a linker group may be bonded to all the linker bond carbon atoms, or a linker group may be bonded to some of the linker bond carbon atoms and the rest may remain. A hydroxy group may be bonded to the carbon atom of the linker bond portion of. It is more preferable that a linker group is bonded to all the linker bond carbon atoms.

Similarly, the drug to be delivered is bound to the other end of the linker group, which is different from the end bound to the metal acene complex, but the drug is bound to all of the multiple linker groups. Alternatively, the drug may be bound to only some of the linker groups. In the case of the metal halide acene complex, one molecule or two molecules of the drug can be bonded per one molecule of the metal ace complex, and it is more preferable that two molecules of the drug are bonded. In the case of the metal-acene complex dimer, 1 to 4 molecules of the drug can be bonded per 1 molecule of the metal-acene complex, and it is more preferable that 2 or more molecules (for example, 2 molecules) of the drug are bonded. When two molecules of drug are bound to the metal-acene complex dimer, the first drug molecule is bound to one monomer and the second drug molecule is bound to the other monomer. Is preferred.

The linking mode between the linker compound or linker group and the drug can be appropriately selected by those skilled in the art based on ordinary knowledge. For example, the linker group can be attached to the drug molecule via a sulfhydryl group, amino group, carboxyl group, carbonyl group, or hydroxy group on the drug molecule. In other words, the linker compound may have a group capable of forming a bond with these groups at a terminal other than the terminal that bonds to the metal acene complex.

More specifically, the drug delivery system composition of the present embodiment, the compound having the above partial structure,
Formula (III) below:
Or the following formula (IV):
A metal acene complex-drug conjugate represented by In the formula, A is a halide ion, preferably F, Cl, Br, or I, more preferably Cl or Br, and particularly preferably Cl. M is a metal ion selected from the group consisting of Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd, Fe, Mn, Cr, or Cu is preferable, and Fe is particularly preferable. More preferably, the drug delivery system composition comprises a metal acene complex-drug conjugate of formula (III).

Each of R ^{1 to} R ⁶ is a hydrogen atom or a linker group derived from a linker compound having a group capable of forming a bond with a hydroxy group. In the case of the metal halide acene complex of formula (III), at least one of R ¹ and R ² is a linker group rather than a hydrogen atom. More preferably, both R ¹ and R ² are linker groups rather than hydrogen atoms. In the case of the metal acene complex dimer of the formula (IV), at least one of R ^{3 to} R ⁶ is a linker group instead of a hydrogen atom. It is more preferable that two or more of R ^{3 to} R ⁶ are not hydrogen atoms but linker groups, and that three or more are not hydrogen atoms but linker groups, and all four are hydrogen atoms. More preferably, it is a linker group.

Groups capable of forming a bond with a hydroxy group are known to those skilled in the art, and suitable examples thereof include, but are not limited to, a carboxyl group, a chloroformate group, and an isocyanate group. Carboxyl groups and chloroformate groups are particularly preferred. Upon reaction with the hydroxy group, the carboxyl group forms a carboxylic acid ester bond, the chloroformic acid ester group forms a carbonic acid ester bond, and the isocyanate group forms a urethane bond. Many linker compounds having a reactive group referred to in the present disclosure, including these reactive groups, are known to those skilled in the art, and are commercially available, and those skilled in the art can appropriately synthesize them. You can also

O ^* is an oxygen atom derived from the hydroxy group bonded on the metal acene complex. When any of R ^{1 to} R ⁶ is a hydrogen atom, O ^* forms a hydroxy group together with the hydrogen atom. When any of R ^{1 to} R ⁶ is a linker group derived from a linker compound capable of forming a bond with a hydroxy group, O ^* forms the bond with the linker compound. It does not exclude the possibility that the same linker structure as this linker group is formed from other reaction routes not necessarily involving a hydroxy group, and as long as the structures are the same, the linker structure falls within the scope of the present embodiment. It should be understood to be included.

At least one of R ¹ and R ² is a linker group attached to the agent to be delivered at a terminus other than the terminus attached to O ^* . That is, at least one linker group is a linker-drug conjugate. It is preferred that both R ¹ and R ² are linker groups that are attached to the drug at a terminus other than the terminus attached to O ^* . Similarly, at least one of R ^{3 to} R ⁶ is a linker group attached to the drug at a terminus other than the terminus coupled to O ^* . Preferably, two or more (e.g. two) of R ³ to R ^6, more preferably three or more, more preferably all four is combined with the drug in another end terminated bound to O ^* Linker group. When two of R ^{3 to} R ⁶ are linker groups bonded to a drug, it is preferable that R ³ and R ⁶ are the two drug-bonding linker groups.

In one embodiment, the linker group attached to the drug at a terminus other than the terminus attached to O ^* is attached to the drug via a sulfhydryl group on the drug. In other words, the linker compound may have a group capable of forming a bond with a sulfhydryl group, at a terminal other than the terminal at which the metal acene complex is bonded. Examples of groups that can form a bond with a sulfhydryl group include, but are not limited to, maleimide groups, haloacetyl groups, and pyridyl disulfide groups. Maleimide groups are particularly preferred.

In one specific embodiment, among R ^{1 to} R ⁶ , the linker group bonded to the drug has a structure represented by the following formula (V):
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure represented by the following formula (VI),
In the formula, * represents a bond to the above O ^* , X is the above bonded drug, and S is a sulfur atom derived from the above sulfhydryl group. When the drug is bound via its sulfhydryl (SH) group as in this example, the H atom is lost compared to the original drug structure before the bond. In the present disclosure, both the structure before the bond containing the H atom and the structure after the bond without the H atom (that is, the structure of the bonding group derived from the original (free) drug) are referred to as “drug” and “drug”. May be referred to as "X", "X", etc. The same applies to bonding modes other than sulfhydryl groups.

Two or more kinds of drugs X having different structures may be contained in the metal acene complex-drug conjugate. For ^example, one or more of R 1 to R ² or ^R 3 to R ⁶ has a first agent as ^X, or another one of R 1 to R ² or ^R 3 to R ⁶ is, It may have a second agent as X (eg L-cysteine). Of R ^{1 to} R ⁶ , all groups other than the linker group bonded to the drug are preferably groups represented by formula (VI) (that is, a linker group not bonded to the drug). The linker compound for this embodiment may have a structure represented by formula (VII) below.

In another embodiment, the linker group attached to the drug at an end other than the end attached to O ^* is attached to the drug via an amino group on the drug. In other words, the linker compound may have a group capable of forming a bond with an amino group at a terminal other than the terminal that bonds to the metal acene complex. Examples of groups capable of forming a bond with an amino group include, but are not limited to, 4-nitrophenoxy group, N-hydroxysuccinimide (NHS) ester group, sulfo-NHS ester group, and imidoester group. Not done. The 4-nitrophenoxy group is particularly preferred.

In one specific embodiment, among R ^{1 to} R ⁶ , the linker group bonded to the drug has a structure represented by the following formula (VIII):
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure represented by the following formula (IX),
In the formula, * represents a bond to O ^* , X represents the bonded drug, and N ^** represents a nitrogen atom derived from the amino group. Of R ^{1 to} R ⁶ , all groups other than the linker group bonded to the drug are preferably groups represented by formula (IX) (that is, a linker group not bonded to the drug). The linker compound for this embodiment may have a structure represented by formula (X) below.

The specific structure of the linker group and the linker compound and the specific type of the associated reactive group can be appropriately selected by those skilled in the art based on common knowledge and on the specific delivery agent. In particular, the combination of reactive groups linking the drug to be delivered and the linker can be chosen by the user as appropriate for the particular application. Examples of compounds that may be used as linker compounds in various embodiments include, but are not limited to, 3-maleimidopropionic acid, 4-nitrophenyl chloroformate, 2-maleimidoacetic acid, 4-maleimidoacetic acid. Maleimidobutyric acid, 5-maleimidopentanoic acid, 6-maleimidohexanoic acid, 3-cyclohexene-1-carboxylic acid, 4-methyl-3-cyclohexene-1-carboxylic acid, 4-cyclohexene-1,2-dicarboxylic acid, 5- Norbornene-2-carboxylic acid, acrylic acid, crotonic acid, methacrylic acid, 3-cyclopentene-1-carboxylic acid, 5-norbornene-2-carboxylic acid, 19-maleimido-17-oxo-4,7,10,13- Tetraoxa-16-azanonadecanoic acid.

In the linker compound, the group that binds to the hydroxy group on the metal acene complex and the group that binds to the drug are directly bound to each other, or between both groups, typically 20 angstroms or less, preferably 10 angstroms. Sub-Angstrom spacers may be present. Various structures of spacers are known to those skilled in the art, and these are based on a hydrocarbon chain, and may optionally contain non-carbon atoms such as oxygen atom, nitrogen atom, and sulfur atom.

The drug is typically a drug with some pharmacological activity. However, a molecule such as a prodrug that acquires a pharmacological activity only after being subjected to some additional treatment or processing after delivery, or a radioactive substance or a fluorescent substance only for the purpose of in-vivo tracking detection may be a drug in the present embodiment. .. Therefore, the presence of the pharmacological activity of the drug is not essential in this embodiment. Examples of agents include, but are not limited to, polypeptides, peptides, enzymes, antibodies, antigens, oligonucleotides, nucleic acids, radioactive molecules, fluorescent molecules, antibiotics, anesthetics, and other pharmaceutical compounds. The drug of the present embodiment is preferably a non-tumor drug. That is, it is preferable that the drug of the present embodiment is not a drug for the purpose of killing cancer tissue/tumor tissue or inhibiting its growth. It is preferable that the drug of the present embodiment itself has low cytotoxicity or acytotoxicity. Therefore, it is preferable that the whole metal-acene complex-drug conjugate containing the metal-acene complex, the linker, and the drug has low cytotoxicity or non-cytotoxicity.

A drug having a sulfhydryl group or a derivative thereof before being bound to a linker is preferable. Examples include penicillamine, captopril, thiamazole, thiopronin, glutathione, cysteine (especially L-cysteine), acetyl cysteine, methyl cysteine, ethyl cysteine, and any peptide and polypeptide containing cysteine residues (eg papain). A drug having an amino group or a derivative thereof before being bound to a linker is also suitable. As an example, procaine, tetracaine, lidocaine, mepivacaine, dibucaine, bupivacaine, ropivacaine, levobupivacaine, benzylpenicillin, amoxicillin, piperacillin, cefcapene pivoxil, cefditoren pivoxil, cefdinir, Sefebimu, minocycline, doxycycline, tosufloxacin, garenoxacin, Penicillamine, salazosulfapyridine, bucillamine, lobenzarit, methotrexate, mizoribine, leflunomide, azathioprine, cyclophosphamide, cyclosporine, etenzamid, lornoxicam, meloxicam, acetaminophen, etodolac, celecoxib, trastuzumab, carmustine, thiamastine, thiamastine, thiamaxin. Cysteine, acetyl cysteine, methyl cysteine, ethyl cysteine, cystine, cephalosporin, sulfadimethoxine, sulfamonomethoxine, sulfisoxazole, sulfadoxine, sulfamethoxazole, sulfadiazine, sulfachlorpyridazine sodium, sulf Famelazine sodium, zanamivir, oseltamivir, etenzamid, diclofenac, bromelain, cathepsin, caspase, calpain, ibritumomab, bortezomib, rituximab, imatinib, gefitinib, nibinib, nibini, nibini, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger, niger. , Nilotinib, crizotinib, ceritinib, sorafenib, trametinib, bortezomib, carfilzomib, perindopril, delapril, enopril, benazepril, imidapril, fliboxamine, paroxetine, sertraline, glimepiride, ameliprid, natemriprin, carmezodine, carmezodine, carmezodine, carmezodine, carmezolib , Anagliptin, exenatide, lixisenatide, repaglinide, and peptides and polypeptides.

The molecular weight of the drug is preferably 200,000 or less, more preferably 30,000 or less, further preferably 5,000 or less, and particularly preferably 1,000 or less.

In addition to the metal halide acene complex or the metal acene complex dimer as a magnetic carrier and the drug to be delivered, the composition of each of the above embodiments may contain other pharmaceutically acceptable components. Examples include, but are not limited to, water, liposomal lipid layers, and/or pharmaceutically acceptable excipients. Further specific examples of other ingredients that may be included include alcohols (eg ethanol and/or isopropanol), glycerin, polyethylene glycol, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, dextrins, sugars (eg sucrose, lactose, and glucose). One or more), sugar alcohol, magnesium stearate, silica, talc, mineral oil, fat and oil, fatty acid, colorant, flavoring agent, sweetening agent, and preservative, but are not limited thereto. The composition of the present embodiment preferably contains no magnetic carrier other than the metal halide acene complex or the metal acene complex dimer.

Hereinafter, the embodiments will be described more specifically by showing examples, but the present disclosure is not limited to these examples.

[Magnetic measurement]
FIG. 1a shows a result of magnetic property evaluation of an iron acene complex dimer (acacen) performed using a superconducting quantum interference device (SQUID) Quantum Design Inc. MPMS. The results obtained from the corresponding iron salen complex dimers are also shown for comparison. The structures of the iron-acene complex dimer (left) and the iron-salen complex dimer (right) are shown below.

From Fig. 1a, the iron-acene complex dimer shows a particularly strong saturation magnetic susceptibility at a low temperature of 5K, and also at 310K, although it is paramagnetic, it has a significantly higher magnetic susceptibility than the iron-salen complex dimer. You can see that

FIG. 1b shows the results of evaluating the magnetic properties of an iron chloride acene complex having the following structure by the same measurement method as described above.

With reference to FIG. 1b compared to FIG. 1a (note the difference in scale on the vertical axis), the iron chloride-acene complex is far superior to the iron-acene complex dimer and far exceeds the iron-salen complex dimer. It can be seen that it has a high magnetic susceptibility.

[Cytotoxicity evaluation]
OVK18 cells, which is a human ovarian cancer cell line, were seeded in a 96-well plate at a cell density of 1.0×10 ⁴ cells/well (n=4). After culturing at 37° C. under standard conditions of 5% CO ₂ for 2 hours, the same iron salen complex dimer, iron acene complex dimer, and iron chloride acene complex as described above were added at 2.5 mg/L, The cells were administered at 5 mg/L or 10 mg/L. 17 hours later, 50 μL of an XTT reagent to which 1/50 of the activation reagent of the XTT assay kit (ATCC, Model No. 30-1011K) for quantifying living cells was added was added per well. After further culturing for 2 hours, the absorbance in the range of 490 to 655 nm was measured with a plate reader. The doubling time of OVK18 cells is about 48 hours.

The results are shown in Figure 2. The cell survival rate is a percentage of the number of viable cells calculated based on the number of viable cells in the non-administration control as 100%. In the sample administered with the iron-salen complex, the cell survival rate was lower than 20% as compared to the non-administered control (Control) to which only physiological saline was added at any dose, which showed a high antitumor effect (cell killing). Effect) was confirmed. In contrast, the antitumor effect of the iron acene complex dimer was remarkably low, and the cell viability of more than 50% was maintained at the dose of 2.5 mg/L. The cell viability when the iron chloride acene complex was administered was higher, and the cell viability was maintained at more than 80% at all doses, and the iron chloride acene complex has substantially no antitumor effect. Was shown. As described above, it was revealed that the iron-acene complex dimer and the iron chloride-acene complex have low cytotoxicity or cytotoxicity, unlike the metal complexes conventionally known as antitumor agents.

[Synthesis example 1]
The metal halide acene complex can be synthesized according to the following scheme. The synthesis of iron chloride acene complexes is also described in Bull. Chem. Soc. Jpn., 50(1), 119-122 (1977).

A stirring bar and acetylacetone (40 mmol) are put into a 10 mL two-necked flask, ethylenediamine (20 mmol) is added dropwise with stirring, and the mixture is stirred at room temperature for a while. Suction filtration is performed while washing with hexane, and the residue is dried under reduced pressure to obtain an acene ligand (H ₂ acacen ligand) with a yield of about 99%.

A stirrer and the above-mentioned acene ligand (1.1 g, 0.005 mol) were put into a 200 mL two-necked flask, one port was connected to a vacuum nitrogen line, and the other was covered with a rubber septum. To do. While stirring, 40 mL of dehydrated methanol (methanol) was added and dissolved, and further, a solution of anhydrous FeCl ₃ (0.8 g, 0.005 mol) dissolved in 40 mL of dehydrated methanol was added at room temperature. Triethylamine (1.4 mL, 0.01 mol) is added here. This is heated at 60° C. for 10 minutes and then left at room temperature overnight. Suction filtration is performed while washing the obtained crystals with cold methanol to obtain an iron chloride acene complex (Fe(acacen)Cl) with a yield of about 50%. According to this scheme, the kinds of metal atom and halogen atom in the metal complex can be appropriately changed based on the ordinary knowledge of those skilled in the art.

[Synthesis example 2]
The metal acene complex dimer can be synthesized according to the following scheme.

The iron chloride acene complex (0.16 g, 0.5 mmol) obtained as described above is dissolved in 10 mL of dichloromethane (CH ₂ Cl ₂ ) to obtain a purple solution. Then, 0.5 mol/L KOH aqueous solution is added to the obtained solution until the aqueous layer changes from purple to orange. The reaction solution is depressurized, the organic layer is concentrated, and the mixture is left in a refrigerator overnight. The precipitate is suction filtered while washing with hexane and dried under reduced pressure to obtain about 0.20 g of dimer crystals of iron-acene complex dimer containing dichloromethane.

[Elemental analysis and powder X-ray measurement]
The results of elemental analysis of the iron chloride acene complex and the iron acene complex dimer synthesized according to the above scheme are shown in the following table together with the corresponding theoretical values.

The powder X-ray measurement results of the obtained iron chloride acene complex and iron acene complex dimer are shown in FIG. 3 together with the corresponding calculated values (calc). A Co radiation source was used as the measurement radiation source.

From these results, it was confirmed that an iron chloride acene complex and an iron acene complex dimer were synthesized.

[Synthesis example 3]
Synthesis of a metal halide acene complex having a linker group and a drug bound thereto can be performed according to the following scheme.

Step 1:
First, a hydroxy group is introduced at the α-position of the ketone of compound 1 by the so-called Davis oxidation reaction described in F. Davis et al., J. Am. Chem. Soc., 112, 6679-6690 (1990). To Compound 1 is added a solution of sodium bis(trimethylsilyl)amide in THF (tetrahydrofuran) (0.6 mL, 1M). A solution prepared by dissolving 0.5 mmol of Compound 1 in 0.3 mL of THF is added dropwise and stirred for 30 minutes. Further, a solution prepared by dissolving 187 mg (0.75 mmol) of (+)-(camphorylsulfonyl)oxaziridine in 3 mL of THF is added dropwise. After 15 minutes, at −78° C., 3 mL of saturated NH ₄ I aqueous solution and 10 mL of diethyl ether were added to terminate the reaction, and the temperature was returned to room temperature. The organic layer is washed with saturated Na ₂ S ₂ O ₃ and saturated aqueous NaCl solution, dried over anhydrous MgSO ₄ , and suction filtered. Pentane is added to the obtained mixture and suction filtration is performed to remove the by-product camphorsulfomine. Purification by flash chromatography gives compound 2.

Compound 3, which is a linker compound, can be obtained as described in Tetrahedron 63 (2007) 6404-6414.

Step 2:
The procedure after step 2 is essentially the same as that conventionally used for salen complexes. Linking of the linker group is performed as described in Tetrahedron 63 (2007) 6404-6414. First, a solution is prepared by dissolving 0.1 M of N,N-dimethylaminopyridine in THF (20 mL). In this solution, compound 2 (99.4 mg, 0.338 mmol), compound 3 (121.9 mg, 0.721 mmol), diisopropylcarbodiimide (170 μmol) as a dehydration condensing agent, and NaHCO ₃ (75 mg, 0.89 mmol). And stir at room temperature for 2 hours. The liquid obtained by concentrating the reaction solution is purified by column chromatography on silica gel (20 g) using a 1:1 mixed solvent of ethyl acetate (ethyl acetate) and hexane as a developing solvent to obtain Compound 4.

Step 3:
An iron chloride complex is prepared as described in Bull. Chem. Soc. Jpn., 50(1), 119-122 (1977). A stir bar and compound 4 (2792.7 mg, 5 mmol) are placed in a 200 mL two-necked flask, and vacuum nitrogen substitution is performed. While stirring, 40 mL of dehydrated methanol was added and dissolved, and further, a solution of anhydrous FeCl ₃ (0.8 g, 0.005 mol) in 40 mL of dehydrated methanol was added at room temperature. Triethylamine (1.4 mL, 10 mmol) is added here. This is heated at 60° C. for 10 minutes and then left at room temperature overnight. Suction filtration is performed while washing the obtained crystals with cold methanol to obtain compound 5.

Step 4:
According to the conventional method described in Tetrahedron 63 (2007) 6404-6414, a drug having a sulfhydryl group is bound to the linker group of compound 5. In this example, protein as drug X (10 mg of lyophilized papain purchased from Sigma-Aldrich) and L-cysteine (10 mg) are put in water (H ₂ O, 1 mL) and stirred for 30 minutes. Then, phosphate buffer (300 μL, 1M, pH=7.01) is added and stirred. Then, 6 hours after stirring, the compound 6 in which papain (X) is bound to at least one of the linker groups is obtained.

[Synthesis example 4]
The metal acene complex dimer having a linker group and a drug bound thereto can be synthesized according to the following scheme.

Step 4':
The above compound 5 (324.9 mg, 5 mmol) is dissolved in dichloromethane (10 mL), and subsequently 1 mL of 0.5 mol/L KOH is added and stirred. The reaction solution is concentrated and left in the refrigerator overnight. The precipitate is suction filtered while washing with hexane. The obtained solid is dissolved in dichloromethane, and hexane is added for recrystallization. Compound 7 is obtained by suction filtration and drying under reduced pressure.

Compound 7, the protein X as a drug X (10 mg of lyophilized papain purchased from Sigma-Aldrich) and L-cysteine (10 mg) were put in water (H ₂ O, 1 mL) and stirred for 30 minutes. Then, phosphate buffer (300 μL, 1M, pH=7.01) is added and stirred. Then, 6 hours after stirring, the compound 8 in which papain (X) is bound to at least one of the linker groups is obtained.

In Synthesis Examples 3 and 4, the specific structure (for example, chain length) of the linker compound, the type of reactive group that forms a bond with the acene structure and the drug, and the type of the drug X depend on the specific application. The trader can make appropriate changes based on ordinary knowledge. Similarly, the types of metal atom and halogen atom in the metal complex can be appropriately changed by those skilled in the art based on ordinary knowledge.

For example, 4-nitrophenyl chloroformate can be used as a linker compound instead of the compound 3 as in the coupling reaction between the amino group of the aminated salen complex and the hydroxy group of paclitaxel in Non-Patent Document 2. In this case, the chloroformate group at one end forms a carbonate bond with the hydroxy group on the acene complex, then the other end reacts with the amino group on the drug to form a urethane bond. Also, depending on the specific structure used, there may be a reaction sequence in which the drug and the linker group are bound in advance and then it is bound to the acene complex.

[Synthesis example 5]
The above compound 2 can also be obtained by utilizing the reaction described in Angew. Chem. Int. Ed. 53, 548-552 (2014) as follows.

Step 1':
Cs ₂ CO ₃ (0.1 mmol), P(OEt) ₃ (1.0 mmol), and DMSO (2 mL) were added to the above compound 1 (112 mg, 0.5 mmol), and under an oxygen atmosphere (normal pressure), Stir at room temperature for 48 hours to give compound 2.

[Synthesis example 6]
The above compound 2 can also be obtained by utilizing the reaction described in Bull. Chem. Soc. Jpn., 51(1), 335-336 (1978) as follows.

Step 1'':
Acetylacetone (6.007 g, 0.06 mol) is dissolved in a mixed solution of acetic acid (50 mL) and acetic anhydride (5 mL), and the mixture is stirred at 30°C. 5 mL of sulfuric acid was added, and 2 g of (diacetoxyiodo)benzene was added at intervals of 30 minutes so that the temperature was kept at 30° C. (total amount: 0.05 mol). After stirring for 6 hours at 30° C., extract 3 times with 100 mL of water and concentrate the extract. Potassium bromide is added to the concentrate to precipitate white crystals of diallyl iodonium salt. Extract 3 times with 100 mL of chloroform or diethyl ether and concentrate under reduced pressure. The concentrated solution is distilled under reduced pressure to obtain compound 9.

A stirring bar and compound 9 (6.326 g, 0.04 mol) are put into a 10 mL two-necked flask, ethylenediamine (1.20 g, 0.02 mol) is added dropwise with stirring, and the mixture is stirred at room temperature for a while. Suction filtration is performed while washing with hexane, and the residue is dried under reduced pressure to obtain compound 10.

Compound 10 is dissolved in ethanol, an aqueous NaOH solution is added, and the mixture is stirred. The compound 2 is obtained by neutralizing with an aqueous acid solution.

Embodiments of the present disclosure may be useful in the fields of medicine, veterinary medicine, medicine, and biomedical research.

Claims (9)

A drug delivery system composition for delivering a drug to a target tissue while allowing the target tissue to survive, comprising:
Formula (I) below:
Or the following formula (II):
A metal acene complex structure represented by the following is included as a magnetic carrier, wherein A is a halide ion, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os. , Ir, Pt, Nd, Sm, Eu, and Gd are metal ions selected from the group consisting of:
Composition. The composition of claim 1, wherein M is Fe, Mn, Cr, or Cu. A drug delivery system composition for delivering a drug to a target tissue while allowing the target tissue to survive, comprising:
The following formula (I')
Or the following formula (II')
In the formula, the wavy line is a bonding point, A is a halide ion, M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, A metal ion selected from the group consisting of W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd,
Composition. Formula (III) below:
Or the following formula (IV):
A metal acene complex represented by
A is a halide ion,
M is a metal ion selected from the group consisting of Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu, and Gd,
R ^{1 to} R ⁶ are each a hydrogen atom or a linker group derived from a linker compound having a group capable of forming a bond with a hydroxy group,
O ^* is an oxygen atom derived from a hydroxy group on the metal acene complex and forms a hydroxy group with the hydrogen atom, or forms a bond with the linker compound,
At least one of R ¹ and R ² , and at least one of R ^{3 to} R ⁶ is a linker group bonded to the drug at a terminal other than the terminal bonded to the O ^*. ,
The composition according to claim 3. The composition according to claim 3 or 4, wherein the M is Fe, Mn, Cr, or Cu. 5. The composition of claim 4, wherein a linker group attached to the drug at a terminus other than the terminus attached to the O ^* is attached to the drug via a sulfhydryl group on the drug. Of R ^{1 to} R ^6, the linker group bonded to the drug has a structure represented by the following formula (V):
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure of a linker group represented by the following formula (VI),
In the formula, * represents a bond to the O ^* , X represents the bonded drug, and S represents a sulfur atom derived from the sulfhydryl group,
The composition according to claim 6. 5. The composition of claim 4, wherein a linker group attached to the drug at an end other than the end attached to the O ^* is attached to the drug via an amino group on the drug. Of R ^{1 to} R ^6, the linker group bonded to the drug has a structure represented by the following formula (VIII),
The other of R ^{1 to} R ⁶ is a hydrogen atom or has a structure of a linker group represented by the following formula (IX),
In the formula, * represents a bond to the O ^* , X is the bonded drug, and N ^** is a nitrogen atom derived from the amino group,
The composition according to claim 8.